Cyclooxygenase-2 (COX-2) derived prostaglandins in embryo and embryonic stem cell (ESC) development and survival

Wu先生は30年間アメリカで研究生活を送られたのち現在は台湾においてアメリカのNIHに相当する組織の長という要職をつとめておられます。現在も様々な研究を展開されておられますが今回は長年続けてこられたCOX-2についてお話頂きます。
COX-2 occupies a pivotal position in synthesis of biologically active prostaglandins. Overexpression of COX-2 has been causally linked to inflammatory disorders, cancer, atherosclerosis and neurodegenerative disorders. On the other hand, COX-2 derived PGS such as PGI2 protects cells from apoptosis. Our recent work shows that PGI2 production by endothelial cells (EC) via COX-2 protects ECs from apoptosis via PPARα-mediated 14-3-3upregulation. COX-2 derived PGI2 plays a crucial role in murine embryo development in vitro. The action of PGI2 is also mediated via PPARα as two-cell embryos derived from PPARα knockout mice exhibit a retarded development into mature blastocytes and has impaired implantation. PGI2-type membrane receptor, IP is less important. However, two-cell embryos from IP-/- mice develop in a slower rate than two-cell embryos from wild-type mice. COX-2 plays a crucial role in protecting mouse ESC from apoptosis. However, mESCs do not have detectable PGI synthase and do not produce PGI2. In contrast, they express PGE synthases and produce abundant PGE2. Our recent work suggests that COX-2 derived PGE2 protects ESC from apoptosis via EP2 receptor-mediated Akt activation. Work is in progress to determine whether PGE2 and PGD2 are involved in regulating ESC renewal, proliferation and differentiation.